Interferon (IFN) is a drug having extensive biological effects such as an antiviral effect, an antitumor effect and an immune regulatory effect and is used for treatment of various malignant neoplasms, treatment of diseases owing to viral infection and the like. However, since IFN has a short in vivo half-life, administration of IFN alone does not give sufficient expected efficacy. At present, when IFN-β is used for treatment of chronic hepatitis C, it is administered once a day every day. In recent years, however, it was reported that efficacy of IFN-β is enhanced by administering IFN-β not once a day but twice a day in a half dose (Okushin et al., Liver, Vol. 36, p. 735, 1995). Accordingly, it is considered that it is important to maintain a blood concentration of IFN in order to develop the efficacy of IFN. Namely, it is desirable to increase in vivo stability of IFN and to maintain the blood concentration of IFN. Modification of IFN with macromolecular materials has been made so far for this purpose. For example, an IFN-polyethylene glycol (PEG) conjugate having an enhanced in vivo half-life of IFN was reported (Japanese Laid-open Patent Publication No. 192300/1994). However, its clinical utility is unknown at the present time. Accordingly, an IFN preparation having increased in vivo stability and a maintained blood concentration is desired.
On the other hand, it is also important to make IFN act on a target site specifically for improving the efficacy of IFN (i.e. targeting of a drug). Modification of IFN with macromolecular materials has been made so far for this purpose. For example, an IFN-α-pullulan conjugate increasing accumulation (targeting) of IFN to a liver (Tabata, Y. et al., J. Interferon and Cytokine Research, 19, 287–292, 1999) was reported.
It was reported that IFN has an inhibitory effect on angiogenesis, and its effectiveness for tumor-induced neovasculature was also reported (Sidky, Y. A. et al., Cancer Res., 47, 5155–5161, 1987). Further, its effectiveness was reported for age-related macular degeneration (Fung, W. E., Am. J. Ophthalmol., 112, 349, 1991), neovascular glaucoma (Miller, J. W. et al., Ophthalmology, 100, 9, 1992), diabetic retinopathy (Wakelee-Lynch, J. and Banks, P., Diabetes Care, 15, 300, 1992) and the like in diseases in an ophthalmological field.
As mentioned above, however, since IFN has short duration in blood and has no organ specificity either, free IFN does not exhibit sufficient effects expected as an angiogenesis inhibitor. Accordingly, it is necessary to modify IFN in some degree so that the duration of IFN in blood is prolonged and IFN acts specifically on tissues having neovasculature, particularly tumors or ophthalmic tissues having neovasculature.
Though the above-mentioned IFN-α-pullulan conjugate increases the accumulation (targeting) of IFN in the liver, the conjugate is not formed so that IFN exhibits the inhibitory effect on angiogenesis sufficiently, namely IFN acts specifically on the tissues having neovasculature, particularly the tumors or theophthalmic tissues having neovasculature. Though pullulan increases in vivo half-life, it has short duration in blood since it tends to accumulate in a liver (Yamaoka, T. et al., Drug Delivery, 1, 75–82, 1993). However, this feature does not make IFN exhibit the inhibitory effect on angiogenesis sufficiently.
An object of the present invention is to provide modified IFN so that the duration of IFN in blood is prolonged and IFN acts specifically on the tissues having neovasculature, particularly the tumors or the ophthalmic tissues having neovasculature.